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Anthracycline-Induced Cardiotoxicity: Molecular Insights Obtained from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs).

ABSTRACT: Anthracyclines are a class of chemotherapy drugs that are highly effective for the treatment of human cancers, but their clinical use is limited by associated dose-dependent cardiotoxicity. The precise mechanisms by which individual anthracycline induces cardiotoxicity are not fully understood. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are emerging as a physiologically relevant model to assess drugs cardiotoxicity. Here, we describe an assay platform by coupling hiPSC-CMs and impedance measurement, which allows real-time monitoring of cardiomyocyte cellular index, beating amplitude, and beating rate. Using this approach, we have performed comparative studies on a panel of four anthracycline drugs (doxorubicin, epirubicin, idarubicin, and daunorubicin) which share a high degree of structural similarity but are associated with distinct cardiotoxicity profiles and maximum cumulative dose limits. Notably, results from our hiPSC-CMs impedance model (dose-dependent responses and EC₅₀ values) agree well with the recommended clinical dose limits for these drugs. Using time-lapse imaging and RNAseq, we found that the differences in anthracycline cardiotoxicity are closely linked to extent of cardiomyocyte uptake and magnitude of activation/inhibition of several cellular pathways such as death receptor signaling, ROS production, and dysregulation of calcium signaling. The results provide molecular insights into anthracycline cardiac interactions and offer a novel assay system to more robustly assess potential cardiotoxicity during drug development.

SUBMITTER: Bozza WP

PROVIDER: S-EPMC7956936 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Anthracycline-Induced Cardiotoxicity: Molecular Insights Obtained from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs).

Bozza William P WP Takeda Kazuyo K Alterovitz Wei-Lun WL Chou Chao-Kai CK Shen Rong-Fong RF Zhang Baolin B

The AAPS journal 20210314 2

Anthracyclines are a class of chemotherapy drugs that are highly effective for the treatment of human cancers, but their clinical use is limited by associated dose-dependent cardiotoxicity. The precise mechanisms by which individual anthracycline induces cardiotoxicity are not fully understood. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are emerging as a physiologically relevant model to assess drugs cardiotoxicity. Here, we describe an assay platform by coupling hiPS ...[more]

PMID: 33719006

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Project description:Introduction: Cardiotoxicity is one of the leading causes of compound attrition during drug development. Most in vitro screening platforms aim at detecting acute cardio-electrophysiological changes and drug-induced chronic functional alterations are often not studied in the early stage of drug development. Therefore, we developed an assay using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that evaluates both drug-induced acute and delayed electrophysiological and cytotoxic effects of reference compounds with clinically known cardiac outcomes. Methods: hiPSC-CMs were seeded in 48-well multielectrode array (MEA) plates and were treated with four doses of reference compounds (covering and exceeding clinical free plasma peak concentrations -fCmax values) and MEA recordings were conducted for 4 days. Functional-electrophysiological (field-potentials) and viability (impedance) parameters were recorded with a MEA machine. Results: To assess this platform, we tested tyrosine-kinase inhibitors with high-cardiac risk profile (sunitinib, vandetanib and nilotinib) and low-cardiac risk (erlotinib), as well as known classic cardiac toxic drugs (doxorubicin and BMS-986094), ion-channel trafficking inhibitors (pentamidine, probucol and arsenic trioxide) and compounds without known clinical cardiotoxicity (amoxicillin, cetirizine, captopril and aspirin). By evaluating the effects of these compounds on MEA parameters, the assay was mostly able to recapitulate different drug-induced cardiotoxicities, represented by a prolongation of the field potential, changes in beating rate and presence of arrhythmic events in acute (<2 h) or delayed phase ≥24 h, and/or reduction of impedance during the delayed phase (≥24 h). Furthermore, a few reference compounds were tested in hiPSC-CMs using fluorescence- and luminescence-based plate reader assays, confirming the presence or absence of cytotoxic effects, linked to changes of the impedance parameters measured in the MEA assay. Of note, some cardiotoxic effects could not be identified at acute time points (<2 h) but were clearly detected after 24 h, reinforcing the importance of chronic drug evaluation. Discussion: In conclusion, the evaluation of chronic drug-induced cardiotoxicity using a hiPSC-CMs in vitro assay can contribute to the early de-risking of compounds and help optimize the drug development process.

Project description:IntroductionDilated cardiomyopathy is a major cause of progressive heart failure. Utilization of stem cell therapy offers a potential means of regenerating viable cardiac tissue. However, a major obstacle to stem cell therapy is the delivery and survival of implanted stem cells in the ischemic heart. To address this issue, we have developed a biomimetic aligned nanofibrous cardiac patch and characterized the alignment and function of human inducible pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) cultured on this cardiac patch. This hiPSC-CMs seeded patch was compared with hiPSC-CMs cultured on standard flat cell culture plates.MethodshiPSC-CMs were cultured on; 1) a highly aligned polylactide-co-glycolide (PLGA) nanofiber scaffold (~50 microns thick) and 2) on a standard flat culture plate. Scanning electron microscopy (SEM) was used to determine alignment of PLGA nanofibers and orientation of the cells on the respective surfaces. Analysis of gap junctions (Connexin-43) was performed by confocal imaging in both the groups. Calcium cycling and patch-clamp technique were performed to measure calcium transients and electrical coupling properties of cardiomyocytes.ResultsSEM demonstrated >90% alignment of the nanofibers in the patch which is similar to the extracellular matrix of decellularized rat myocardium. Confocal imaging of the cardiomyocytes demonstrated symmetrical alignment in the same direction on the aligned nanofiber patch in sharp contrast to the random appearance of cardiomyocytes cultured on a tissue culture plate. The hiPSC-CMs cultured on aligned nanofiber cardiac patches showed more efficient calcium cycling compared with cells cultured on standard flat surface culture plates. Quantification of mRNA with qRT-PCR confirmed that these cardiomyocytes expressed α-actinin, troponin-T and connexin-43 in-vitro.ConclusionsOverall, our results demonstrated changes in morphology and function of human induced pluripotent derived cardiomyocytes cultured in an anisotropic environment created by an aligned nanofiber patch. In this environment, these cells better approximate normal cardiac tissue compared with cells cultured on flat surface and can serve as the basis for bioengineering of an implantable cardiac patch.

Dataset Information

Anthracycline-Induced Cardiotoxicity: Molecular Insights Obtained from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs).

Publications

Anthracycline-Induced Cardiotoxicity: Molecular Insights Obtained from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs).

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